Abstract
Hypoxia is an important cause of brain injury in ischemic stroke. It is known that endoplasmic reticulum (ER) stress is an important determinant of cell survival or death during hypoxia. However, the signaling pathways and molecular mechanisms involved remain to be studied in more detail. To investigate whether inhibition of ER stress promotes neuroprotection pathways, we applied an in vitro oxygen–glucose deprivation (OGD) followed by reoxygenation model of human SK-N-MC neuronal cell cultures in this study. Our results showed that neuronal cell death was induced in this model during the OGD reoxygenation by the sustained ER stress, but not during OGD phase. However, treatment of the cultures with lithium with the OGD reoxygenation insult did not result in neuroprotection, whereas concomitant treatment of chemical chaperon 4-phenylbutyric acid (4-PBA) provides protective effects in ER stress-exposed cells. Moreover, 4-PBA rescued ER stress-suppressed Akt protein biosynthesis, which works cooperatively with lithium in the activation of Akt downstream signaling by inhibition of autophagy-induced cell death. Taken together, our finding provides a possible mechanism by which 4-PBA and lithium contribute to mediate neuroprotection cooperatively. This result may potentially be a useful therapeutic strategy for ischemic stroke.
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Acknowledgments
This work was supported by Grants from the Chung Shan Medical University-Tungs’ Taichung Metroharbor Hospital (CSMU-TTM-098-003), and from the Ministry of Science and Technology (101-2320-B-040-015-MY3). The fluorescence microscope and imaging analyzer were performed at the Instrument Center of Chung Shan Medical University, which is supported by the Ministry of Science and Technology, Ministry of Education, and Chung Shan Medical University.
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Tung, WF., Chen, WJ., Hung, HC. et al. 4-Phenylbutyric Acid (4-PBA) and Lithium Cooperatively Attenuate Cell Death during Oxygen–Glucose Deprivation (OGD) and Reoxygenation. Cell Mol Neurobiol 35, 849–859 (2015). https://doi.org/10.1007/s10571-015-0179-5
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DOI: https://doi.org/10.1007/s10571-015-0179-5